Sequential Chemotherapy Proves Better Than Alternating Regimen in Node-Positive Breast Cancer

June 1, 1995

LOS ANGELES--Sequential chemotherapy including an anthracycline produced better overall and relapse-free survival in women with node-positive breast cancer (more than three nodes) than did an alternating schedule of the same drugs, Gianni Bonadonna, MD, of the Istituto Nazionale Tumori, Milan, reported at the ASCO annual meeting.

LOS ANGELES--Sequential chemotherapy including an anthracyclineproduced better overall and relapse-free survival in women withnode-positive breast cancer (more than three nodes) than did analternating schedule of the same drugs, Gianni Bonadonna, MD,of the Istituto Nazionale Tumori, Milan, reported at the ASCOannual meeting.

The sequential adjuvant regimen consisted of four courses of doxorubicinfollowed by eight cycles of CMF (cyclophosphamide, methotrexate,and fluorouracil). The alternating schedule called for two coursesof CMF interspersed with one cycle of doxorubicin.

These 10-year results confirm and extend the Milan trial's 5-yearfindings, reported previously, said Dr. Bonadonna, director, Divisionof Medical Oncology. "Our data on Adriamycin followed byCMF are sufficiently mature and valid to advise replacing in clinicalpractice the classical CMF with Adriamycin followed by CMF inthe adjuvant treatment of women with more than three positivenodes," he said.

About two thirds (67%) of the 403 women in the study (all aged70 years or less with resectable primary breast tumors and morethan three positive axillary lymph nodes) underwent a modifiedradical mastectomy, and 33% had breast-conserving surgery withfull axillary node dissection followed by postoperative irradiation.

Within 4 weeks of surgery, patients were randomized to eitherthe sequential or alternating chemotherapy regimen. Both regimenswere repeated every 3 weeks for a total duration of 33 weeks.

The dose of doxorubicin used, 75 mg/m², was considered afull adjuvant dose in patients with breast cancer at the timeof the study's inception in the early 1980s, Dr. Bonadonna noted.Doses for the other agents were 600 mg/m² of cyclophosphamide,40 mg/m² of methotrexate, and 600 mg/m² of fluorouracil.

The rate of relapse-free survival at 10 years was significantlyhigher in patients treated with sequential therapy than in thosegiven alternating therapy (42% vs 28%), as was the 10-year overallsurvival rate (58% vs 44%), Dr. Bonadonna reported. Median relapse-freesurvival was about twice as long in the sequential vs the alternatinggroup (86 vs 46 months).

"The median total survival has not been reached at 10 yearsin the sequential group, while it was 7.3 years in the alternatinggroup," Dr. Bonadonna said.

Sequential chemotherapy influenced survival to a similar extentin pre- and postmenopausal women. In contrast, the effects ofalternating chemo were more favorable in premenopausal than inpostmenopausal women (median relapse-free survival duration, 58vs 29 months).

These results indicate that "when we are dealing with veryeffective chemotherapy, there is no difference between pre- andpostmenopausal women," Dr. Bonadonna said. However, whentreated with moderately effective regimens, which is how he characterizedthe alternating protocol, premenopausal women fare better thanpostmenopausal women.

Both tumor size and the number of positive nodes affected relapse-freesurvival in the Milan study. The use of sequential chemotherapyapparently leveled the playing field with regard to these prognosticfactors, however.

"Sequential chemotherapy improved outcome to the point thatthe course of disease in women having worse prognostic indicatorswho received sequential therapy was superimposable to that ofwomen with less severe indicators who were given alternating therapy,"he said.

Overall, the more intensive sequential regimen was well tolerated,but congestive heart failure did occur in four patients on thisarm, two of whom died.

Delay Radiation Therapy

Three of the four patients who developed cardiomyopathy had receivedpostoperative irradiation to the left breast, which, in this study,was given concomitantly with adjuvant chemotherapy in most patients.As a result, Dr. Bonadonna advised clinicians to delay radiationtherapy until after the completion of adjuvant chemotherapy.

"The superiority of sequential over alternating chemotherapycan be explained by the intensity of Adriamycin administration,as well as by the use of full dose and sequencing of two effective,known non-cross-resistant combinations," Dr. Bonadonna said."Whatever mechanism is behind these reported results, schedulingis a promising approach for the design of subsequent clinicalstudies."